Preclinical in vivo proof-of-concept for cyclic oligopeptide rescuers of pathogenic protein misfolding and aggregation associated with neurodegeneration

Introduction

Within the ERC Consolidator Grant ProMiDis, my team and I have developed genetically engineered bacteria that function as a stand-alone, living discovery platform for short, drug-like cyclic peptides rescuing the misfolding and aggregation of proteins associated with human diseases (protein misfolding diseases, PMDs).

Discoveries and Applications

By applying this technology, we have discovered hundreds of new molecules—putative drugs against notorious PMDs, such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). We have filed patent applications for aspects of this technology and for the first set of bioactive molecules.

Project Goals

In PoC4ProMis, we will demonstrate in vivo proof-of-concept for the most promising molecules targeting the devastating neurodegenerative disease ALS. To achieve this, we will:

1. Develop an optimized method for efficient delivery of cyclic peptides to the central nervous system (CNS) by utilizing a novel specialized CNS delivery vehicle.
2. Evaluate the effectiveness of our lead molecules to reverse disease phenotypes in well-established ALS mouse models.
3. Explore opportunities to strengthen our IP portfolio by patent-protecting our SOD1-targeting cyclic peptides with additional claims relating to method-of-use and mode of delivery.

Conclusion

PoC4ProMis will demonstrate in vivo proof-of-concept and will provide a general approach for efficient CNS delivery of cyclic peptide drugs targeting additional neurodegenerative diseases of high priority for drug development.